雷特（RETT）综合症启示

时间:2015-03-17 21:45来源:未知

Scientists from Harvard Medical School haveconnected the single gene mutated in Rett syndrome with a surprising function.Harrison Gabel and Benyam Kinde talk about their discovery. Video: HMS OCER 来自哈佛医学院的专家们已经连接简单基因突变与雷特综合症令人惊讶的功能。Harrison Gabel and Benyam Kinde谈论他们的发现。Video:HMS OCER

It’s a long story。说来话长

Scientists have known for 15 years thatmutations in a single gene lead to Rett syndrome, a severe neurologicaldisorder that affects girls around their first birthdays. In the years sincethe MECP2 gene was pinpointed, researchers have struggled to understand how itfunctions in the brain in Rett syndrome.科学家们已经了解了15年关于单个基因突变导致雷特综合症，严重的神经系统失调在大约一周岁左右影响女孩们。自从这些年MECP2基因已经被准确找出，研究致力于理解它如何在雷特综合症患者大脑中作用。

Now the enigma of Rett syndrome and perhapsother disorders on the autism spectrum could be one step closer to beingsolved.现在这个雷特综合症之谜和其它自闭障碍可以进一步得到解决

Get more HMS news here. 从这得到更多HMS资讯

A Harvard Medical School team has discoveredthat when MECP2 is mutated in Rett syndrome, the brain loses its ability toregulate genes that are unusually long. Their finding suggests new ways toconsider reversing the intellectual and physical debilitation this disruptioncauses with a drug that could potentially target this error. The team, led byMichael Greenberg, reported its findings in Nature.一个哈佛医学团队已经发现，当MECP2在RETT综合症患者上变异，大脑失去调节基因的能力，基因异乎寻常地长。他们的发现暗示着新方法去考虑扭转由于这种毁坏造成的智力和身体的虚弱，一种以此错误为潜在目标的药物。这个团队，由Michael Greenberg带领，将其研究结果发布在《自然》杂志上。

“The longer the gene, the more disrupted itbecomes when you lose MECP2,” said Greenberg, the Nathan Marsh Pusey Professorof Neurobiology at HMS. “Rett syndrome may be a defect in this process offine-tuning the expression of long genes.” “越长基因，当失去MECP2越多中断”Greenberg说，the NathanMarsh Pusey Professor of Neurobiology at HMS.“雷特综合症可能是一个在这个调整过程中表达长基因的缺陷”

Scientists, including Greenberg, have figuredout over the last 10 years that MECP2 plays a role in sculpting the connectionsbetween neurons in the developing brain. These synapses are refined by exposureto sensory experiences, just the sort of stimulation a one-year-old wouldencounter as she learns to walk and talk. 科学家们，包括Greenberg，已经在过去10年中指出MECP2扮演一个雕刻角色，在大脑发育过程中连接神经元。这些突触被暴露于感观体验，只是那种刺激一岁碰到她学习走路和说话。

MECP2 is present in all cells in the body, butwhen the brain is forming and maturing its synapses in response to sensoryinput, MECP2 levels in the brain are almost 10 times as high as in other partsof the body. The new study connects MECP2 mutations to long genes, which may bemore prone to errors simply because their length leaves more room for mistakes.MECP2存在于身体的所有细胞，但当大脑正在形成和成熟突触正在响应感觉输入，MECP2在大脑中的水平几乎是身体其它部位的10倍。这项新研究联接MECP2突变至长基因，它可能更容易出错，因为它们的长度留有更多空间犯错。

Speed Bump减速带“Normally, MECP2 may act like a speed bump,fine-tuning long genes by slowing down the machinery that transcribes longgenes,” said Harrison Gabel, a postdoctoral fellow in the Greenberg lab andco-first author of the Nature paper. In transcription, the information in astrand of DNA is copied onto a new molecule of messenger RNA, which is thenturned into a protein. “Without MECP2, the machinery may be moving too fast,making too much mRNA from these genes, resulting in problems for the neurons.” “通常，MECP2可能扮演类似减速带，通过降低机器整度细调长基因，转录长基因” Harrison Gabel说，Greenberb试验室博士后研究员和自然杂志第一作者。在转录,DNA链中的信息复制到一个新的信使RNA分子,然后变成一种蛋白质。“没有MECP2,机器可能会移动太快,制造太多从这些基因mRNA,导致神经元的问题”

Finding this effect of MECP2 on long genes wasno small feat. In a typical search for the mechanism behind a genetic mutation,mice are engineered to lack the normal gene so that its absence reveals how itfunctions. However, work in many different labs has shown that knocking outMECP2 had only subtle effects when analyzed across the genome. The changes ingene expression were inconsistent, small and, using Gabel’s word, “fuzzy.” 发现MECP2在长基因上的影响是不小的壮举。在典型研究关于基因变异机制，老鼠被设计成缺少正常基因，因此它没有揭示它的功能如何。然而，许多不同试验室的工作已经表明，当分析染色体时MECP2移出只有微妙的影响。在基因表达上的改变是不一致的，小而且，用Gabel的话说“模糊的”

Gabel took another approach, querying massivegenomic databases such as ENCODE to ask a simple question: What do genes thatare affected by mutated MECP2 have in common? Gabel采用另一种途径，查询大量的基因数据库，比如ENCODE来问一个简单问题：由变异的MECP2影响的基因有什么共同之处？

Answer: They are long. Most of them are at leastfive times longer than the average gene, with many of them more than 50 timeslonger than the average. It is important to note that the genes identifiedacross dozens of data sets were very long, giving the researchers a commonfinding where previous conclusions from these data sets had lacked a commontheme.答案：他们很长。他们中大部分的长度是平均基因长度的至少5倍，其中他们中很多长达50倍。注意到这个很重要，基因鉴定通过成千上万数据集会很长，给予研究者一个共同发现，之前从这些数据集得到的结论缺乏一个共性。Harrison and co-first author Benyam Kinde, anMD-PhD student in the Greenberg lab, found the long-gene misregulation inmultiple mouse models of Rett syndrome and confirmed it in the brain tissue ofdeceased Rett patients.Harrison和第一作者Benyam Kinde，Greenberg试验室医学博士生，发现在多个老鼠样本中长基因被误调节，并且在已故雷特患者的脑组织中得到确认。For MECP2 to function normally as a speed bump,it binds to a form of methylated DNA found in long genes in the brain. Methylgroups are chemical modifiers of gene activity, and in other parts of the bodyMECP2 binds methylated CG sites on genes. The methylation pattern that appearsto be important for MECP2 in regulating long genes is known as methylated CA,and there appears to be a special mechanism operating as synapses are forming.因为MECP2正常功能是减速带，它与甲基DNA以捆绑形式出现在大脑的长基因中。甲基原子团是基因活性的化学修复器，其它身体部分的MECP2与甲基CG捆绑在基因上。甲基化模式，好象是对MECP2非常重要，在调节长基因被称作甲基化CA，似乎有一个特殊的机制操作作为突触形成“It seems that evolution has used MECP2 and methylatedCA to put in place this speed bump so that the expression of long genes isrestrained in the brain,” Greenberg said. “As far as Rett syndrome, the thought is nowthat this subtle but widespread overexpression of long genes might becontributing to the disorder.” “看来,进化用MECP2和甲基化CA来安置这个减速带，以便约束长基因在大脑中的表达。” Greenberg说。“就雷特综合症而言，现在这种微妙而广泛的超表达的长基因可能导致混乱

Corrective Strategy纠正策略The scientists can’t be sure of what theseoverexpressed long genes do, but many of them appear to be very important tothe function of the brain. This suggests that if they could correct the defectin long-gene expression, they might be able to reverse at least some of thesymptoms of Rett syndrome. As a first attempt at a corrective strategy, theresearchers selected a cancer drug called topotecan because it blocks an enzymeknown to be important for long-gene transcription.科学家们还不确定这些超表达长基因干了些什么，但他们许多显示对大脑功能非常重要。这个暗示如果他们能修正长基因缺陷表达，他们可能至少可以逆转一些雷特综合症的症状。作为纠正策略的首次尝试，研究人员选择了一种癌症药物称作topotecan，因为它阻断一种已知的酶，它对长基因转录非常重要。

In a lab dish, they added topotecan to neurons lackingMECP2. The drug reversed the long-gene misregulation, suggesting that restoringnormal long-gene expression might be a way to correct neurological dysfunctionin Rett syndrome and in other autism spectrum disorders with long genes, suchas fragile X syndrome. Topotecan, a chemotherapeutic agent, is too toxic,Greenberg said, but derivatives of topotecan might be a worthwhile avenue topursue.在实验室培养皿，他们加topotecan 给缺乏MECP2的神经原，这药逆转了长基因的误调节，表明恢复正常基因表达可能是一种方法来纠正雷特的神经机能障碍和其它孤独证谱系障碍，例如脆性X综合症。 Topotecan,一种化学疗药，也是毒药， Greenderg说，但topotecan的衍生物可能是值得研究的方向。

“We think this issue of long-gene misregulation may bemore generally occurring in other disorders of human cognition,” Greenbergsaid. “The potential is pretty significant because one now has a commonregulatory mechanism to target with drugs.” “我们认为长基因的误调节可能普遍发生在其它已知的人类认知障碍，”Greenberg说，潜力是重大的，因为现在有一个共同的调节机制去以药物为目标。

This work wassupported by grants from the Rett Syndrome Research Trust and the NationalInstitutes of Health (1RO1NS048276 andT32GM007753), the Damon Runyon Cancer Research Foundation (DRG-2048-10), theWilliam Randolf Hearst fund and the Howard Hughes Medical Institute.